DK164771B - PROCEDURE FOR THE PREPARATION OF A NATIONAL PHARMACEUTICAL PREPARATION CONTAINING ERGOT-CYCLIC PEPTIDAL KALOIDS - Google Patents

Description

DK 164771 B

The present invention relates to nasal pharmaceutical compositions.

The practice of administering certain pharmacologically active agents such as broncholytics and hormones nasally to achieve systemic absorption has been known for a long time (see pages 722-729 in "Pharmazeutische 5 Technologie" edited by H. Sucker, P. Fuchs and P. Speiser, Georg Thieme Verlag, Stuttgart, 1978). Nasal systemic administration of pharmacologically active agents may offer significant benefits over other routes of administration. For example, the active agent enters directly into the bloodstream after passage of the nasal mucosa, leading 10 to immediate bioavailability in the blood of the active agent and a rapid onset of therapeutic action. There are nasal aerosol applicators available that are capable of providing a precise dose of the active agent in liquid or powder spray form with a droplet or particle size suitable for use and which are easy to use. Nevertheless, the nasal route to systemic administration of pharmacologically active agents is still not common.

British Patent Specification No. 1,592,563 discloses that certain ergot-cyclic peptide alkaloids can be advantageously administered by the nasal route. There are disclosed nasal pharmaceutical compositions of dihydroergotamine, in particular in the form of liquids and powders which can be used to provide an appropriate spray. A representative nasal pharmaceutical composition contemplated by the above patent is an aqueous solution containing 4 mg / ml dihydroergotamine mesylate, 50 mg ethanol and 150 mg glycerin, and this composition will be referred to hereinafter as "reference" solutions.

Pharmaceuticals formulated for nasal administration are often found to be unsatisfactory in widespread clinical use.

For example, they may be unstable over a longer period of time, are not well tolerated or are not well accepted by patients. An important factor for poor tolerance may be that a component of the composition, perhaps the active agent, suppresses the twitching hair function.

The ciliary hairs of the respiratory tract are microscopic hair-like structures with a length of approx. 7 / an and a diameter of 1-3 µm. These twigs

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2 is located on the surface layer of the mucosa of the nose and the trachea. The twine hairs make undulating movements with a stroke frequency of approx.

300-900 beats per per minute at 37 ° C, which mucus coalesces with dust particles and other foreign matter toward the passageways of the nose 5 (choanae) associated with the pharanx, or forward toward the nostril openings. Thus, the particles and material are either suctioned or trimmed. The mucus layer can move at a speed of approx. 2-10 mm per minute in some animals. In studies conducted by I.B. Andersen et al., In American Review of Respiratory Disease 106, 438 (1977), found in a 10 group of people an average mucosal flow rate of 4.8 mm per minute. The individual flow rates ranged from 0 to 23.6 mm per second. minute.

Thus, it will be obvious that any substance that suppresses the twitch hair function interferes with one of the body's important protective mechanisms.

The degree to which a nasally administered agent suppresses the ciliary hair function can be observed by standard tests, e.g., in vitro, using ciliary trachea from animals.

One reproducible and sensitive test is as follows: The trachea or nasal septum of a guinea pig or rabbit is removed immediately after killing. The organ is immersed in physiological balance serum (Dulbecco) at 23 ° C. A tubular fragment, e.g., of three trachea rings, is removed and the feather hair epithelium is scraped off. The stroke rate of the cadaver hairs at one particular location is measured by micro-photo oscillographic techniques according to the principles of L. Chevance et al.

Acta Otolaryng, 70, 16-28 (1970), where the pubic hairs are observed and enlarged .500 times. A change in the stroke rate indicates a change in the feather hair function.

Some pharmacologically active agents, in particular dihydroergotamine, suppress gut hair function. Thus, application (about 0.1-0.3 ml) of the "reference" solution or an aqueous solution containing 4 mg / ml dihydroergotamine mesylate to the pubic hair results in an irreversible suppression of the pubic hair beats within 2 minutes of application.

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Further, the claimants have found that xanthines which are non-toxic, enhance the mucosal hair function, by increasing the mucosal beat frequency in the test described above, can be used to at least partially counteract the mimic hair function suppressing effects of other ingredients in a pharmaceutical composition and well tolerated nasal pharmaceuticals.

It is also known from Martindale, "The Extra Pharmacopoeia" 26th Edition, 1972, pages 350-352 and 361-362 that ergot alkaloids have an enhanced therapeutic effect when concomitantly administered xanthines.

Such combination preparations are used in the form of tablets, coated tablets, gelatin capsules, granules, suppositories or solutions. Also known from GB Patent No. 1,556,851, AT Patent No. 287,186 and the Medicines Catalog 1981, the Medicines Catalog Copenhagen, page 400, pharmaceutical forms containing both 15 ergot alkaloids and xanthines.

It has now surprisingly been found that xanthines are useful for stabilizing, in particular, nasal pharmaceutical compositions of ergot-cyclic peptide alkaloids, and the present invention therefore relates to a process for preparing a nasal pharmaceutical composition 20 containing ergot-cyclic peptide alkaloids, in that a pharmacologically active agent belonging to the group consisting of ergot-cyclic peptide alkaloids is formulated with a xanthine of the general formula I

0 fl * 3% Ύ>

25 O ^ N ^ r X

R 2 where R 1, R 2 and R 3 are each independently hydrogen or C 1-6 alkyl.

Nasal pharmaceutical compositions prepared by the method of the invention will most preferably be in the form of a liquid or a powder.

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Xanthines of the aforementioned kind are particularly effective in counteracting the suppression of mucosal hair function, e.g., induced by a pharmacologically active agent. Applicants have also found that such xanthines are well tolerated by nasal administration.

Agents that enhance the hair function can be determined by in vitro tests, such as the test described above, and suitably produce a 20% or more increase in the hair function 20 minutes after administration. Of course, the amount of gum hair enhancer present in the composition will depend on the amounts 10 of other ingredients that suppress the gum hair function, the solubility of the agent and the extent to which they suppress the gum hair function. Preferred amounts of cilia hair enhancer in the nasal pharmaceutical composition can be determined by routine experiments, for example, using the aforementioned in vitro test.

Nasal pharmaceutical compositions may be prepared containing such xanthines which are liquid solutions which are stable to, for example, decomposition, precipitation or discoloration at an acceptable osmolarity and pH, and which can be easily sterilized.

The pharmacologically active agent, namely, the group consisting of 20 ergot-cyclic peptide alkaloids, is able to be systemically absorbed through the nasal mucosa and pass into the circulation of the body.

The pharmacologically active agent is an ergot-cyclic peptide alkaloid product described by the general formula I of British Patent Specification No. 1,592,563 to which reference is made, and the agent is especially dihydroergotamine.

The active agent may be administered in free base form or in the form of pharmaceutically acceptable acid addition salts, e.g., the mesylate. Such salts generally have an efficiency of the same magnitude as the active agent. For example, dihydroergotamine may be administered in the form of mesylate.

The specific therapeutic effect exhibited by the pharmacologically active agent is not critical. 1 in view of the rapid increase in the concentration of active agent in the blood after nasal administration.

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5, nasal pharmaceutical compositions prepared by the method of the invention are particularly useful in administering the active agents for the treatment of conditions requiring rapid relief, for example, in particular orthostatic hypotension and especially migraine.

The dosage of the pharmacologically active agent to be administered will, of course, vary from compound to compound. Generally, a satisfactory dose is that which provides the same order of bioavailability or therapeutic effect as that obtained by injecting a therapeutically effective amount of the active agent. Often, the nasal route requires less doses than the oral route to achieve the same effect, for example, a nasal dose may be from ca. 0.5 to approx. 0.01 times the oral dose. For example, for dihydroergotamine 1 mg administered nasally will give approx. the same quantitative effect (as demonstrated by bioavailability studies or 15 vasoconstriction of the veins in the hand) as 10 mg dihydroergotamine administered orally. For dihydroergotamine, the preferred amount to be administered nasally is of the order of approx. 0.25 to 5 mg.

Of course, the dose of active agent should not be so high, or the dose 20 should not be repeated so often that side effects may occur.

in

The substance which is capable of stabilizing the composition and at the same time enhancing the twitch hair function is, as indicated above, a xanthine of the general formula I as defined above.

Such xanthines are generally known. Examples of suitable xanthines include theophylline and the preferred xanthine is caffeine.

The exact amount of xanthine to be administered in a dose will include depending on the extent to which the pharmacologically active agent and any other ingredient present in the nasal pharmaceutical composition suppress the pubic hair function. The ratio of active agent to xanthine can vary within wide limits and can be determined by routine experimentation. An appropriate ratio is from approx. 0.1: 1 to approx. 10: 1. It is preferred

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6 to use the minimum amount of xanthine which can bring the hair dye function within 50 to 100% of the baseline value (for untreated hair hair) within 20 minutes of application in the aforementioned in vitro hair dye function test.

5 Satisfactory results have been obtained from approx. 1 mg to approx. 5 mg xanthine per dosage.

The nasal composition may contain, e.g. 0.2 to approx. 2% by weight, preferably 0.5 to 2% by weight xanthine, for example in a liquid with, for example, 4 g dihydroergotamine liter.

It is preferred to administer a nasal spray which is isotonic or which is slightly hypertonic to the mucosal mucus. The osmotic pressure of the liquid providing the spray is conveniently from about 200 to 600 mOsm, especially from 280 to 360 mOsm per second. liter.

The desired osmotic pressure can be obtained by the addition of any nontoxic isotonizing agent. For example, sodium chloride can be used. It is preferred to use a non-toxic sugar, especially glucose.

The exact amount of isotonizing agent present depends, inter alia, on of the osmotic strength of the specific isotonizing agent 20 and the osmotic pressure of the other components of the nasal pharmaceutical composition.

For example, the weight ratio of xanthine to isotonicant may be off. ca. 1: 0.05 to approx. 1:10.

For a sugar, a typical amount is from approx. 5 mg to 50 mg per dosage.

The weight ratio of xanthine to the sugar is, for example, from approx. 1: 1 to approx.

1:10, This can correspond to from approx. 1 to approx. 10%, for example 2.5 to 5% for liquid compositions. For sodium chloride, an appropriate weight ratio of xanthine to sodium chloride is, for example, from about. 1: 0.5 to approx.

1: 1. For liquid compositions, an appropriate concentration of about 0.7 to approx. 1.2%.

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The nasal pharmaceutical composition prepared by the process of the invention may be in liquid form. A solvent such as water may be used. A co-solvent such as propylene glycol may be present, preferably at a concentration of less than 10%, for example 0.1-10%. The composition is preferably in the form of an aqueous solution. Alternatively, it may be in the form of a suspension or an oil-in-water emulsion.

If desired, the nasal pharmaceutical composition of the invention may be in powder form. The powder is preferably composed such that it dissolves rapidly upon contact * with the mucosa. The powder is suitably amorphous in that the crystals present therein are of a very small size.

If desired, other nasal pharmaceutical excipients may be present. The precise choice of other excipients present depends on a variety of factors, including the stability and tolerability of the resulting pharmaceutical compositions. The influence of several excipients has been described in the literature, for example in H.J.M. van de Donk et al., First European Congress of Biopharmacy and Pharmacokinetics 1-3. April 1981, edited by J.M. Aiache and J. Hirtz, Cler-20 mont. Ferrant, pages 406-413. For example, there may be an antioxidant or preservative such as sodium metabisulphate or methyl parahydroxybenzoate or preferably benzalkonium chloride, cetylpyridinium chloride or phenododecinium bromide, sodium benzoate, sodium propionate or sodium sorbate or a protective gas such as carbon dioxide present or present.

The weight ratio of antioxidant or preservative to xanthine is preferably kept very low, e.g. 0.2: 1 to approx. 0.02: 1st For example, the concentration of antioxidant or preservative in a liquid can be from 0.001 to 0.2%.

If desired, a surfactant such as sorbitan monooleate may be present. Of course, the amount of pharmaceutical excipients in the composition is suitably kept as low as possible, e.g. 5% of the amount of xanthine.

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When the nasal pharmaceutical composition is in solid form, an inert carrier may be used which may comprise e.g. 97.5 to 85% of the composition. Alternatively, no inert carrier may be necessary.

The final pH of the nasal preparation is preferably from about 3.5 to 5 approx. 9, suitably 3.5 to 4.5 in the case of dihydroergotamine.

The desired pH can be obtained by the presence of a buffer system, for example acetic acid / sodium acetate, CO2 / HCO3 'or HPO4 "/ H2PO4" and pbs buffer.

The nasal pharmaceutical compositions may be formulated in conventional manner, for example, by mixing the ingredients, for example, to form a solution in water, followed, if desired, by filtration of the solution and / or sterilization under conventional conditions, e.g., by heating. If a powdered pharmaceutical composition is desired, a lyophilisate is preferably prepared by subjecting a cooled solution of the nasal pharmaceutical composition to a vacuum.

Conveniently, the nasal pharmaceutical compositions are packaged in a nasal spray applicator designed to produce a spray of the composition. If desired, pressure from a compressed gas, e.g., air, nitrogen or a hydrocarbon such as 20 friend or ultrasonic means, may be used to provide the spray. The applicator may be designed to receive a unit dosage form, e.g., an ampoule, capsule or the like containing a sufficient amount of the nasal pharmaceutical composition prepared by the method of the invention to a single dose. Alternatively, the vial may be of sufficient volume, eg 0.5 to 10 ml, to provide separate doses of the nasal pharmaceutical composition. Numerous convenient nasal spray applicators are known, e.g., "Microcompack" from Aerosol Services AG, CH-4313 Moehlin, Switzerland, or applicators from Valois S.A., BG G-26110 Le Neubourg, France, both of which provide liquid sprays.

The ampoule can be broken before inserting into the nasal spray applicator.

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If the nasal pharmaceutical composition is a liquid, the volume of the preparation to be dispensed in a single dose may vary between wide limits. A suitable volume is from 0.1 to 0.2 ml. The particle size of the spray is preferably greater than 800 μιη, e.g. 800 to 1000 μπι.

When the nasal pharmaceutical composition is solid, the volume and particle size of the preparation to be administered in a single dose may also vary widely. The volume is preferably in the range of about 0.1 and the particle size is 10 from ca. 800 to approx. 1000 μπι.

For the preferred active agent dihydroergotamine, the ratio of xanthine to the active agent is conveniently from ca. 1: 0.1 to approx.

1: 1. Preferably, the pharmaceutical composition is in the form of a solution containing from ca. 0.2 to approx. 2% by weight, eg 0.5 to 2% -15% of the xanthine. Glucose is suitably present.

A particularly preferred variant of the invention is that a nasal pharmaceutical composition is prepared which contains an aqueous solution of 0.4% dihydroergotamine mesylate, 5% glucose and 1% caffeine.

This preparation will hereinafter be referred to as Preparation A.

The mucociliary action of caffeine in the nasal pharmaceutical preparations can be determined by conventional means by standard in vitro and in vivo tests. A particularly convenient in vitro assay is described above. Another test can be performed according to the principles described by R. Guillerm, Il Fårmaco, 1, 1-18 (1972). A piece of sheep or 25 rat air tubes containing feather hair and mucus is stretched out on a thermostatically controlled plate at 35 ° C. The nasal pharmaceutical composition is sprayed onto the trachea by means of an ultrasonic aerosol delivering 1 ml of solution per ml. liters of air per per minute over a period of 5 minutes. The diameter of the spray nozzle is from 2 to 4 µm. The stroke frequency of the cadaver hairs is measured by photosillographic techniques according to those of R.

Guillerm et al., Physiol. 57, 725 (1965). In this test, the composition A according to the invention has a very small effect on the hair function. An example of the results of the aforementioned Chevance technique is the following:

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Preparation Time after administration 0 5 10 20 30 60 90 min min min min min min min

Fimer hair stroke rate (stroke / minute) 5 ________ 5% glucose 420 480 nt nt nt 420 nt 1% caffeine 340 380 nt 500 nt nt 520 1% caffeine + glucose 320 240 300 420 420 nt nt 10 Preparation A 360 nt 380 300 nt nt nt nt = not tested.

In a further in vitro test, the rate of movement across a mucosal trachea of a sheep is studied according to the principles of S.P.

15 Battista in Screening Methods in Pharmacology, edited by R.A.

Turner and P. Hebborn, Volume 2, Academic Press, New York, 1971, 167-202. The trachea is held in an extended state in a thermoregulated chamber. The rate of movement of a particle across the mucosa is studied, including over an area of the trachea, where approx. 0.1 to 20 0.2 ml of the nasal pharmaceutical preparation has been sprayed.

An example of results obtained with Preparation A is as follows:

Time Experiment 1 Experiment 2 (minutes) 25 0 Spraying 130 μΐ of Preparation A into a zone of 1 cm width and crossing approx. 12 minutes after the starting purctic from which the particle exits.

Throughput Speed Throughput Speed 30 distance (mm / min) distance (mm / min) (mm) (mm) 5 38 7.6 50 10 7 52 7 70 10

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11 91J 70 9 90 10 122) 83 4.3 110 6.7 153) 110 9 140 10 ^^ arrival at spray area; crossing of sprayed area; 3) departure away from sprayed area.

As can be seen, there is only a slight reduction in the velocity of the particle when it crosses over a zone treated with preparation A.

The mucociliary properties of the nasal pharmaceutical composition can also be observed in in vivo tests.

A clinical test was performed to measure the nasal drainage in accordance with the principles described by I. Andersen et al., Am.

Rev. Respir. Haze. 110, 301-305 (1974). In one test, a saccharin grain (0.4 to 0.6 mm in diameter) is placed on the nasal mucosa of healthy volunteers in the area of the middle concha in front of the upper nasolacrimal duct, where the nostrils are most permeable. The time it takes for a subject to experience a sense of sweetness is noted as the mucociliary transit time.

20 Approx. 0.13 ml of a nasal pharmaceutical preparation is injected into the nose. The saccharin bowl is placed in the nose 3 minutes later. 5 minutes; later, the subjects are asked every 30 seconds whether a sense of sweetness has been observed. The average results obtained for 12 subjects were as follows: 25 _

Transit Time3 (Minutes)

Placebo4J 15.2 ± 4.7 Preparation A 13.9 ± 2.6 4)

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12 '0.9% aqueous NaCl solution.

time period from spraying to feeling sweetness. :

Preparation A shortened transit time slightly but not significantly. The composition was generally well tolerated. A slight transient tingling sensation in the nasal mucosa was observed by 1 subject out of 12 with placebo and 2 subjects out of 12 with preparation A.

In another initial test, the "reference" solution was used.

The results obtained were as follows: 10 Transit time ^ * (minutes)

Placebo4 * 15.44 +3.86

Reference 22.50 ± 10.12 15 _ 4) 5)

For the meanings of and see above.

An undesirable 40 to 45% increase in transit time was observed. 4 out of 10 subjects felt irritation. Three out of 10 subjects experienced vasomotor disorders (rhinorrhea and obstruction).

Furthermore, even when the nasal mucosa is provoked with a nasal pharmaceutical composition prepared by the method of the invention, the amount of xanthine absorbed may be low enough to provide a therapeutic effect. For example, in a double-blind clinical trial, a nasal spray of Preparation A was administered to 10 healthy volunteers. The equivalent of 2.6 mg of caffeine was administered. The amount of caffeine measured in the blood in one initial test was as follows:

Area under curve (nanograms / ml / hour) 22.29 ± 3.94 C (nanograms / ml) 2.34 ± 0.52 max °

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Thus, the amount of caffeine measured in the body was 10 to 20 times less than would be expected from consuming 1 cup of coffee (containing, for example, 50-100 mg of caffeine).

The effectiveness of the compositions can be determined by conventional clinical therapeutic tests. For example, with Preparation A, a clinical study has been performed in patients suffering from migraine.

The study was performed with a preparation A and placebo in 9 patients according to a double-blind cross-over schedule. Each patient was treated for 1 month with either Preparation A or Placebo.

Spray applicators designed to administer a metered dose of 0.5 mg dihydroergotamine in the form of Preparation A or a similar volume of Placebo solution were used. At the onset of a migraine attack, each subject administered a metered dose into each nostril. Every 30 minutes, a further dose, 15 if the seizure persists, is administered up to a maximum of 4 doses within 24 hours.

Seven subjects out of 9 experienced a beneficial effect on the migraine attack when treated with Preparation A. With Placebo, only one patient experienced some beneficial effect. Additional data 20 obtained from this test were as follows:

Treatment

Preparation A Placebo 25 Total migraine attacks 41 26

results

Relief of seizures 22 0

Decrease in the intensity of the seizure 5 6

No effect 14 20 30 _____

These results show a statistically significant beneficial effect on the migraine attack of preparation A.

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In a total assessment, the tolerability of Preparation A was excellent in 8 subjects and acceptable in one subject.

As stated above, the nasal pharmaceutical compositions prepared by the method of the invention are stable. Stability can be measured by standard stress stability tests in which the concentration of the active agent is determined. An example of results obtained with Preparation A and the "reference" solution are as follows:

Reference Solution Preparation A

Temperature 35 ° G 44 ° C 50 ° C 35 ° C 44 ° C 50 ° C

10 Weeks Concentration% Concentration% 0 104 104 104 103 103 103 3 99 96 92 102 94 93 6 97.5 90.5 83.5 103 92 88 15 9 93 86 76 101 89 85.

As can be seen from the above results, overall, Composition A is significantly more stable than the reference solution.

In further tests, it was shown that a lyophilizate had excellent stability even at 50 ° C.

In another stability test, a nasal plunger spray applicator placed on a bottle filled with 10 ml of preparation A or the reference solution was used to produce a nasal spray of 0.13 in ml at 11, 21, 31, 61 and 91 days, respectively. filling. After a spray has been produced, air is sucked into the bottle to replace the sprayed solution and the air can consequently induce decomposition.

With preparation A, the concentration of dihydroergotamine was approx. 89% of the original value after 91 days. With the reference solution, the concentration of dihydroergotamine was 81% of the original value after 61 days and 66% of the original value after 91 days.

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Thus, the stability of preparation A is significantly better than the reference solution.

All the percentages and weight ratios stated herein refer to guard parts, except percentages referring to washes, with the 5 entries referring to guard per unit weight. volume of liquid.

The invention is illustrated by the following example:

EXAMPLE

1. Preparation

Ingredients per 1 ml per 10 1 10 Dihydroergotamine mesylate 0.004 g 40 g

Caffeine 0.010 g 100 g

Glucose 0.050 g 500 g

Water to 1 ml of 10 liters.

2. Preparation of the Preparation 15 9 liters of water are matted with carbon dioxide. Dissolve 100 g of caffeine in the water and then 40 g of dihydroergotamine mesylate. 500 g of glucose is dissolved in the stirred solution without stopping the saturation with carbon dioxide. Water is added up to a volume of 10 liters. The mixture is filtered in the presence of carbon dioxide through a filter (0.22 μιη 20 pores).

3. Filling of ampoules

Vials are filled with a maximum of 1 ml of solution under carbon dioxide, sealed and then sterilized in an autoclave at 121 ° C for 5 minutes.

The pH is typically between 4.38 and 4.46 at 22 ° C.

Claims (6)

A process for the preparation of a nasal pharmaceutical composition, characterized in that a pharmacologically active agent belonging to the group consisting of ergot-cyclic peptide alkaloids is formulated with a xanthine of the general formula I0fl R3n-V and R 3 individually represents hydrogen or alkyl. Process according to claim 1, characterized in that the pharmacologically active agent is 15. dihydroergotamine. Process according to claim 2, characterized in that the dihydroergotamine is in the form of the mesylate. Process according to any one of claims 1-3, 20, characterized in that the weight ratio of the active agent to the xanthine is between 0.1: 1 and 10: 1. DK 164771B 4. Application The ampoules are broken open and then inserted into a conventional nasal dispenser. For each dose the dispenser sprays approx. 0.13 ml of solution containing 0.5 mg of dihydroergotamine. The dose is applied nasally 2 to 4 5 times a day by prophylaxis or treatment of migraine. Process according to any one of claims 1-4, characterized in that the xanthine is caffeine. Process according to any one of claims 1-4, characterized in that the xanthine is theophylline. j